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3 - Iron toxicity

Published online by Cambridge University Press:  01 June 2011

James C. Barton
Affiliation:
University of Alabama, Birmingham
Corwin Q. Edwards
Affiliation:
University of Utah Medical Center
Pradyumna D. Phatak
Affiliation:
University of Rochester Medical Center, New York
Robert S. Britton
Affiliation:
St Louis University, Missouri
Bruce R. Bacon
Affiliation:
St Louis University, Missouri
James C. Barton
Affiliation:
University of Alabama, Birmingham
Corwin Q. Edwards
Affiliation:
University of Utah School of Medicine, Salt Lake City
Pradyumna D. Phatak
Affiliation:
University of Rochester Medical Center, New York
Robert S. Britton
Affiliation:
St Louis University, Missouri
Bruce R. Bacon
Affiliation:
St Louis University, Missouri
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Summary

Iron is an essential element, but in excess it can result in cell injury (Table 3.1). When storage mechanisms are overwhelmed, iron in low molecular weight forms can play a catalytic role in the initiation of free radical reactions. The resulting oxyradicals have the potential to damage cellular lipids, nucleic acids, proteins, and carbohydrates, resulting in wide-ranging impairment in cellular function and integrity. The rate of free radical production must overwhelm the cytoprotective defenses of cells before injury occurs.

In HFE hemochromatosis, there can be a pathologic expansion of body iron stores due to an increase in the absorption of dietary iron. Transferrin saturation is increased and non-transferrin-bound iron (which is redox-active) may be present. The excess iron is preferentially deposited in the cytoplasm of parenchymal cells of various organs and tissues including the liver, pancreas, heart, endocrine glands, skin, and joints. Damage can result in micronodular cirrhosis of the liver and atrophy of the pancreas (primarily islets). Hepatocellular carcinoma, usually in the presence of cirrhosis, is another consequence of excess iron deposition in the liver. Symptoms are related to damage of involved organs and include liver failure (from cirrhosis), diabetes mellitus, arthritis, cardiac dysfunction (arrhythmias and failure), and hypogonadotrophic hypogonadism. Important co-factors of iron-induced liver injury include chronic hepatitis C and excess alcohol consumption. Although cadmium and lead may also be transported by divalent metal transporter-1, the major apical iron transporter in enterocytes, excess iron is considered to be the major cause of toxicity in hemochromatosis.

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Publisher: Cambridge University Press
Print publication year: 2010

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References

Britton, RS. Mechanisms of iron toxicity. In: Barton, JC, Edwards, CQ, eds. Hemochromatosis. Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge, Cambridge University Press. 2000; 229–38.CrossRefGoogle Scholar
Pietrangelo, A. Mechanism of iron toxicity. Adv Exp Med Biol 2002; 509: 19–43.CrossRefGoogle ScholarPubMed
Britton, RS, Leicester, KL, Bacon, BR. Iron toxicity and chelation therapy. Int J Hematol 2002; 76: 219–28.CrossRefGoogle ScholarPubMed
Papanikolaou, G, Pantopoulos, K. Iron metabolism and toxicity. Toxicol Appl Pharmacol 2005; 202: 119–211.CrossRefGoogle ScholarPubMed
Ramm, GA, Ruddell, RG.Hepatotoxicity of iron overload: Mechanisms of iron-induced hepatic fibrogenesis. Semin Liver Dis 2005; 25: 433–49.CrossRefGoogle ScholarPubMed
Bacon, BR.Hemochromatosis: Diagnosis and management. Gastroenterology 2001; 120: 718–25.CrossRefGoogle ScholarPubMed
Powell, LW. Hereditary hemochromatosis and iron overload diseases. J Gastroenterol Hepatol 2002; 17 (Suppl 1): 191.CrossRefGoogle ScholarPubMed
Bottomley, SS. Secondary iron overload disorders. Semin Hematol 1998; 35: 77–86.Google ScholarPubMed
Halliwell, B, Gutteridge, JMC. Free Radicals in Biology and Medicine. 3rd edition. Oxford, Oxford University Press, 1999.Google Scholar
Young, IS, Trouton, TG, Torney, JJ, McMaster, D, Callender, ME, Trimble, ER. Antioxidant status and lipid peroxidation in hereditary haemochromatosis. Free Radic Biol Med 1994; 16: 393–7.CrossRefGoogle ScholarPubMed
Niemela, O, Parkkila, S, Britton, RS, Brunt, E, Janney, C, Bacon, BR. Hepatic lipid peroxidation in hereditary hemochromatosis and alcoholic liver injury. J Lab Clin Med 1999; 133: 451–60.CrossRefGoogle ScholarPubMed
Houglum, K, Ramm, GA, Crawford, DHG, Witztum, JL, Powell, LW, Chojkier, M. Excess iron induces hepatic oxidative stress and transforming growth factor β1 in genetic hemochromatosis. Hepatology 1997; 26: 605–10.CrossRefGoogle ScholarPubMed
Kom, GD, Schwedhelm, E, Nielsen, P, Boger, RH.Increased urinary excretion of 8-iso-prostaglandin F2alpha in patients with HFE-related hemochromatosis: A case-control study. Free Radic Biol Med 2006; 40: 1194–200.CrossRefGoogle ScholarPubMed
Livrea, MA, Tesoriere, L, Pintaudi, AM, et al. Oxidative stress and antioxidant status in β-thalassemia major: Iron overload and depletion of lipid-soluble antioxidants. Blood 1996; 88: 3608–14.Google ScholarPubMed
Iancu, TC, Shiloh, H.Morphological observations in iron overload: An update. Adv Exp Med Biol 1994; 356: 255–65.CrossRefGoogle Scholar
Selden, C, Owen, M, Hopkins, JMP, Peters, TJ. Studies on the concentration and intracellular localization of iron proteins in liver biopsy specimens from patients with iron overload with special reference to their role in lysosomal disruption. Br J Haematol 1980; 44: 593–603.CrossRefGoogle ScholarPubMed
Peters, TJ, O'Connell, MJ, Ward, RJ. Role of free-radical mediated lipid peroxidation in the pathogenesis of hepatic damage by lysosomal disruption. In: Poli, G, Cheeseman, KH, Dianzani, MU, Slater, TF, eds. Free Radicals in Liver Injury. Oxford, IRL Press. 1985; 107–15.Google Scholar
O'Connell, M, Halliwell, B, Moorhouse, CP, Aruoma, OI, Baum, H, Peters, TJ.Formation of hydroxyl radicals in the presence of ferritin and haemosiderin. Is haemosiderin formation a biological protective mechanism? Biochem J 1986; 234: 727–31.CrossRefGoogle Scholar
Myers, BM, Prendergast, FG, Holman, R, Kuntz, SM, LaRusso, NF. Alterations in the structure, physicochemical properties, and pH of hepatocyte lysosomes in experimental iron overload. J Clin Invest 1991; 88: 1207–15.CrossRefGoogle ScholarPubMed
Bacon, BR, Park, CH, Brittenham, GM, O'Neill, R, Tavill, AS. Hepatic mitochondrial oxidative metabolism in rats with chronic dietary iron overload. Hepatology 1985; 5: 789–97.CrossRefGoogle ScholarPubMed
Bacon, BR, O'Neill, R, Britton, RS. Hepatic mitochondrial energy production in rats with chronic iron overload. Gastroenterology 1993; 105: 1134–40.CrossRefGoogle ScholarPubMed
Bacon, BR, Healey, JF, Brittenham, GM, et al. Hepatic microsomal function in rats with chronic dietary iron overload. Gastroenterology 1986; 90: 18443.CrossRefGoogle ScholarPubMed
Britton, RS, O'Neill, R, Bacon, BR. Chronic dietary iron overload in rats results in impaired calcium sequestration by hepatic mitochondria and microsomes. Gastroenterology 1991; 101: 806–11.CrossRefGoogle ScholarPubMed
Hershko, C, Link, G, Konijn, AM. Cardioprotective effect of iron chelators. Adv Exp Med Biol 2002; 509: 77–89.CrossRefGoogle ScholarPubMed
Miranda, CJ, Makui, H, Soares, RJ, et al. Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin. Blood 2003; 102: 2574–80.CrossRefGoogle ScholarPubMed
Kowdley, KV. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 2004; 127: S79–86.CrossRefGoogle ScholarPubMed
Okada, S.Iron-induced tissue damage and cancer: The role of reactive oxygen species-free radicals. Pathol Int 1996; 46: 311–32.CrossRefGoogle ScholarPubMed
Park, J-W, Floyd, RA.Lipid peroxidation products mediate the formation of 8-hydroxydeoxyguanosine in DNA. Free Radic Biol Med 1992; 12: 2450.CrossRefGoogle ScholarPubMed
Zhang, D, Okada, S, Yu, Y, Zheng, P, Yamaguchi, R, Kasai, H.Vitamin E inhibits apoptosis, DNA modification, and cancer incidence induced by iron-mediated peroxidation in Wistar rat kidney. Cancer Res 1997; 57: 2410–14.Google ScholarPubMed
Carmichael, PL, Hewer, A, Osborne, MR, Strain, AJ, Phillips, DH. Detection of bulky DNA lesions in the liver of patients with Wilson's disease and primary haemochromatosis. Mutation Res 1995; 326: 235–43.CrossRefGoogle ScholarPubMed
Nair, J, Carmichael, PL, Fernando, RC, Phillips, DH, Strain, AJ, Bartsch, H. Lipid peroxidation-induced etheno-DNA adducts in the liver of patients with the genetic metal storage disorders Wilson's disease and primary hemochromatosis. Cancer Epidemiol Biomarkers Prev 1998; 7: 435–40.Google Scholar
Hussain, SP, Raja, K, Amstad, PA, et al. Increased p53 mutation load in nontumorous human liver of Wilson's disease and hemochromatosis: Oxyradical overload diseases. Proc Natl Acad Sci USA 2000; 97: 12770.CrossRefGoogle ScholarPubMed

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